a) Field of the Invention
This invention relates to novel heterocyclic substituted phenoxyalkylpyrazines, to methods of preparation thereof and to methods of use thereof as antipicornaviral agents; and to intermediates in their preparation and the use of those intermediates as antipicornaviral agents.
b) Information Disclosure Statement
U.S. Pat. No. 4,857,539 to Diana et al., issued Aug. 15, 1989, discloses compounds of the formula; ##STR2## wherein: Y is an alkylene bridge of 3-9 carbon atoms;
Z is N or HC: PA1 R.sub.1 and R.sub.2 are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro, lower-alkoxycarbonyl or trifluoromethyl; and PA1 Het is selected from; ##STR3## which are stated to be useful as antiviral agents. PA1 R.sub.1 is hydrogen or C.sub.1 -C.sub.3 lower-alkyl; PA1 R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1 -C.sub.3 lower-alkyl or halogen; PA1 R.sub.4 is hydrogen, or C.sub.1 -C.sub.3 lower-alkyl; PA1 or pharmaceutically acceptable acid addition salts thereof which are stated to be useful as antiviral agents, particularly against picornaviruses. antiviral PA1 R.sub.2 and R.sub.3 are hydrogen or C.sub.1-4 alkyl; PA1 Alk is C.sub.1-4 alkanediyl; PA1 R.sub.4 and R.sub.5 are hydrogen, C.sub.1-4 alkyl or halo; and Het is ##STR7## R.sub.6 is hydrogen, C.sub.1-6 alkyl; hydroxyC.sub.1-6 alkyl; C.sub.3-6 cyclo- alkyl; aryl; arylC.sub.1-4 alkyl; C.sub.1-4 alkyloxyC.sub.1-4 alkyl; C.sub.3-6 cyclo- alkylC.sub.1-4 alkyl; trifluoromethyl or amino; PA1 each R.sub.7 independently is hydrogen; C.sub.1-6 alkyl; C.sub.1-6 cyclo- alkyl; aryl; arylC.sub.1-4 alkyl; C.sub.1-4 alkyloxyC.sub.1-4 alkyl; C.sub.3-6 cyclo- alkylC.sub.1-4 alkyl or trifluoromethyl; and PA1 each aryl independently is phenyl or phenyl substituted with 1 or 2 substituents each independently selected from halo, C.sub.1-4 alkyl, trifluoromethyl, C.sub.1-4 alkyloxy or hydroxy. The compounds are stated to have antiviral activity. PA1 R.sub.1 and R.sub.2 are each independently chosen from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkyl sulfinyl alkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, difluoromethyl, trifluoromethyl or cyano; PA1 R.sub.3 and R.sub.4 are each independently chosen from hydrogen, alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, hydroxyalkoxy, alkylthioalkyl, alkanoyl, alkanoyloxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxy, cyanomethyl, fluoroalkyl, or halo; PA1 R.sub.5 is alkoxycarbonyl, alkyltetrazolyl, phenyl or heterocyclyl chosen from benzoxazolyl, benzathiazolyl, thiadiazolyl, imidazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, oxazolinyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or substituted heterocyclyl or substituted phenyl; wherein the substitution is with alkyl, halo, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl or fluoroalkyl; or a pharmaceutically acceptable acid addition salt thereof. PA1 R.sub.1 and R.sub.2 are each individually chosen from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinyl alkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, difluoromethyl, trifluoromethyl or cyano; PA1 R.sub.3 and R.sub.4 are each independently chosen from is hydrogen, alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkylthioalkyl, alkanoyl, alkanoyloxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxy, cyanomethyl, fluoroalkyl, or halo; and PA1 R.sub.5 is alkoxycarbonyl, alkyltetrazolyl, phenyl or heterocyclyl chosen from benzoxazolyl, benzathiazolyl, thiadiazolyl, imidazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or substituted heterocyclyl or substituted phenyl; wherein the substitution is with alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, halo, alkoxy, hydroxy, furyl, thienyl, fluoroalkyl or a pharmaceutically acceptable acid addition salts thereof. PA1 Compounds of formula I can be prepared by the reaction of the appropriate hydroxyalkyl furan and the appropriate R.sub.1 --R.sub.2-4 --R.sub.5 -phenol, as described in U.S. Pat. No. 5,242,924, and 5,051,437 incorporated herein by reference, giving a compound of formula II. The compound of formula II is then reacted with a peroxide, such as m-chloroperbenzoic acid (MCPBA) and then reacted with hydrazine, providing a compound of formula I. PA1 Compounds of formula I can also be prepared by reaction of the appropriate R.sub.1 --R.sub.2-4 --R.sub.5 -phenol and the appropriate furanylalkylhalide as described in U.S. Pat. No. 4,942,241, incorporated herein by reference, to form a compound of formula II which is then treated with an oxidizing agent such as dimethyldioxirane, MMPA or MCPBA and then reacting this oxidized intermediate with hydrazine as described above.
R is hydrogen or lower-alkyl of 1-5 carbon atoms, with the proviso that when Z is N, R is lower-alkyl;
U.S. Pat. No. 4,861,791 to Diana et al., issued Aug. 29, 1989 discloses compounds of the formula: ##STR4## wherein R to R.sub.8 represent various radicals and y. The compounds are stated to be useful as antiviral agents, in particular against picornaviruses.
U.S. Pat. No. 5,242,924, to Diana, issued Sep. 7, 1993 from application filed Jul. 2, 1992, discloses compounds of the formula: ##STR5## wherein Y is a bond, or C.sub.1 -C.sub.6 alkylene;
European Patent Application 435381, published Jul. 3, 1991, discloses pyridazinamines of formula: ##STR6## wherein R.sub.1 is hydrogen, C.sub.1-4 alkyl, halo, hydroxy, trifluoromethyl, cyano, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkylcarbonyl or aryl;